Psilocybin, a compound being developed for major depressive disorder, is converted to psilocin after absorption. A single ascending dose study (0.3 to 0.6 mg/kg) found a significant but shallow relationship between psilocin concentration and QTc interval prolongation. At a clinical dose of 25 mg, the mean peak psilocin concentration is 18.7 ng/mL, associated with a mean QTcF change of 2.1 milliseconds (upper 90% confidence interval: 6.6 ms). The upper confidence limit crossed 10 ms at 31.1 ng/mL psilocin. Even at a supraclinical concentration of 60 ng/mL, the mean QTcF increase is 9.1 ms (upper limit 17.9 ms). Psilocin's short half-life (about 4 hours) suggests no accumulation with monthly oral dosing.
Microdosing involves giving human subjects a subpharmacologic dose (1% of the pharmacologic dose or 100 µg, whichever is lower) of an investigational drug to obtain pre–phase 1 pharmacokinetic data. A key concern is nonlinear pharmacokinetics between microdoses and therapeutic doses, but methods to evaluate this nonlinearity are emerging. Currently, about 80% of drugs tested orally and 100% intravenously show scalable pharmacokinetics within a factor of 2. Microdosing has recently been applied in pediatrics, protein-based therapeutics, and intra-arterial microdosing for localized pharmacodynamics. Compared with other predictive methods, microdosing appears to provide a significantly better understanding of pharmacokinetics before phase 1, though the database remains limited.